Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13]C)(=[O:12])[CH:10]=[CH2:11]>[Na]>[CH2:1]([O:8][CH2:11][CH2:10][C:9]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: OCc1ccccc1
Agent: [Na]
Product: O=C(O)CCOCc1ccccc1
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
Sodium metal (249 mg, 10.8 mmol) was added to benzyl alcohol (30 g, 278 mmol) at room temperature under nitrogen and the reaction was stirred for 30 minutes. Methyl acrylate (25.9 ml, 259 mmol) was then added dropwise and the reaction was stirred at room temperature for 18 h. After quenching with saturated aqueous ammonium chloride solution (200 ml) the mixture was extracted with ethyl acetate (2×300 ml) and the combined organic extracts were washed with brine (100 ml), dried over magnesium sulphate and concentrated under reduced pressure. The residual oil was dissolved in ethanol (300 ml) and 1M aqueous sodium hydroxide solution (300 ml) was added dropwise. After 3 hours the ethanol was removed under reduced pressure and the aqueous residue was washed with dichloromethane (200 ml). The aqueous phase was then acidified with 2N aqueous hydrochloric acid (150 ml), extracted with dichloromethane (2×250 ml) and the combined organic extracts were dried over magnesium sulphate and concentrated under reduced pressure. The residual oil was dissolved in 10% aqueous potassium carbonate solution (300 ml), washed with diethylether (300 ml) and the aqueous phase was acidified to pH 1 using concentrated hydrochloric acid. The mixture was then extracted with dichloromethane (2×300 ml) and the combined organic extracts were dried over magnesium sulphate and concentrated under reduced pressure to provide the title compound (44.4 g) as a colourless oil.
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[C:14]([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:10]([C:9]1[CH:12]=[CH:13][C:6]([N:1]2[CH:5]=[N:4][CH:3]=[N:2]2)=[CH:7][CH:8]=1)=[CH2:14]
Reactant: O=Cc1ccc(-n2cncn2)cc1
Reactant: O=C([O-])[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=Cc1ccc(-n2cncn2)cc1
Temperature: 70 °C
Yield: 62.9 %

Procedure:
To a stirred solution of 4-[1,2,4]-triazol-1-yl-benzaldehyde (9.0 g, 52 mmol) in 1,4-dioxane (100 mL), were added K2CO3 (10.76 g, 78 mmol) and methyl triphenyl phosphonium bromide (22.2 g, 62.4 mmol) at ambient temperature. The resultant reaction mixture was heated to 70° C. for 18 h. After completion of the reaction (TLC), the reaction mixture was cooled to ambient temperature and filtered and the obtained filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) to afforded the title compound as a white solid (5.6 g, 63%): ESIMS m/z 172.09 ([M+H]+).
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:11][C:12]([F:22])([F:21])[O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl>C1COCC1>[F:11][C:12]([F:21])([F:22])[O:13][C:14]1[CH:15]=[CH:16][C:17]([NH:18][C:2]2[CH:10]=[N:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:19][CH:20]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1ccncc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccncc1Nc1ccc(OC(F)(F)F)cc1
Temperature: -78 °C
Yield: 9 %

Procedure:
3-Fluoro-isonicotinic acid (50 mg, 0.354 mmol) and 4-(trifluoromethoxy)aniline (62.8 mg, 0.354 mmol) was added to 2 ml dry THF and the mixture was cooled to −78° C. LiHMDS (1 M in THF, 1.24 ml) was added and the mixture was allowed to warm to room temperature over night. Hydrochloric acid (1 M in methanol, 5 ml) was added and the volatiles were removed in vacuo. The crude material was purified by preparative HPLC to give 9.5 mg (32 μmol; 9% yield) of pure desired product. LC-MS (method V): rt=2.69 min; m/z [M+H]+ 299.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]2([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:9]2)=[CH:3][CH:2]=1.S(=O)(O)[O-:31].[Na+].[OH2:35].C(Cl)(Cl)Cl.C(O)(C)C>N1C=CC=CC=1.[Os](=O)(=O)(=O)=O>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][C:8]2([CH2:23][C:24]3[CH:25]=[CH:26][N:27]=[CH:28][CH:29]=3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([OH:35])[CH:9]2[OH:31])=[CH:5][CH:6]=1
Reactant: C1=C(c2ccccc2)c2ccccc2C1(Cc1ccncc1)Cc1ccncc1
Reactant: O=S([O-])O
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: OC1C(Cc2ccncc2)(Cc2ccncc2)c2ccccc2C1(O)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 1,1-Bis(4-pyridinylmethyl)-3-phenyl-1H-indene (1.0 g, 2.7 mmol) in dry pyridine (10 ml) was added osmium tetroxide (1.0 g, 3.9 mmol, dissoleved in ether). The mixture was stirred at room temperature and monitored by TLC. After completion of the reaction, sodium bisulfite (2.0 g), water (20 ml), and pyridine (5 ml) was added. The mixture was stirred for 1 h, and extractd three times with chloroform: isopropanol (4:1). The combined extracts were washed with brine, dried over magnesium sulfater, and evaporated to give 3,3-bis(4-pyridinylmethyl)-2,3-dihydro-1-phenyl-1H-indene-1,2-diol as a yellow solid, 1.15 g.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]2[C:7]=1[C:8]([O:27][CH:28]([F:30])[F:29])=[C:9]([CH2:19][C:20]1[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=1)[C:10]([CH2:17][CH3:18])=[N:11]2.[CH:32]([N:35]1[CH:39]=[CH:38][C:37](B2OC(C)(C)C(C)(C)O2)=[N:36]1)([CH3:34])[CH3:33].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>CN(C)C=O>[F:30][CH:28]([F:29])[O:27][C:8]1[C:7]2[C:12](=[C:13]([F:16])[CH:14]=[CH:15][C:6]=2[O:5][CH2:4][C:3]([OH:2])=[O:31])[N:11]=[C:10]([CH2:17][CH3:18])[C:9]=1[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:37]2[CH:38]=[CH:39][N:35]([CH:32]([CH3:34])[CH3:33])[N:36]=2)=[CH:22][CH:21]=1
Reactant: CC(C)n1ccc(B2OC(C)(C)C(C)(C)O2)n1
Reactant: CCc1nc2c(F)ccc(OCC(=O)OC)c2c(OC(F)F)c1Cc1ccc(Br)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1nc2c(F)ccc(OCC(=O)O)c2c(OC(F)F)c1Cc1ccc(-c2ccn(C(C)C)n2)cc1
Temperature: 140 °C
Yield: 27.2 %

Procedure:
A mixture of [3-(4-bromobenzyl)-4-difluoromethoxy-2-ethyl-8-fluoroquinolin-5-yloxy]acetic acid methyl ester (0.05 g), 1-isopropyl-3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.047 g), tetrakis(triphenylphospine)palladium (0) (0.012 g), N,N-dimethylformamide (0.3 mL) and 2.0M aqueous cesium carbonate solution (0.2 mL) was heated by microwave irradiation at 140° C. for 6 minutes. The mixture was cooled to room temperature, acidified by the addition of 1.0M aqueous hydrochloric acid solution and then extracted with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure. Purification of the residue by preparative reverse-phase HPLC gave title compound (0.014 g).
Reaction SMILES: [Br:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(N(CC)CC)C.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[Br:1][C:2]1[C:3]([CH2:4][OH:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: O=C(O)c1cccnc1Br
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: OCc1cccnc1Br
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90.4 %

Procedure:
To a solution of 2-bromonicotinic acid (4.0 g, 20 mmol) and triethylamine (3.34 mL, 24 mmol, 1.2 eq.) in THF (100 mL) was added i-butyl chloroformate (3.12 mL, 24 mmol, 1.2 eq.) at 0° C. The mixture was stirred at 0° C. for 10 min and filtered. To this filtrate was added a suspension of NaBH4 (1.52 g, 40 mmol, 2 eq.) in water (1.0 mL) at 0° C. The mixture was stirred for 30 min, added water (3 mL), continued to stir for 2 h, and concentrated to dryness. The crude was purified on silica gel using a mixture of ethylacetate and hexanes as eluent to give (2-bromopyridin-3-yl)methanol (3.4 g, 90%) as a white solid. LRMS (M+H+) m/z 188.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][CH2:10][CH2:11][O:12][CH3:13].C([Li])CCC.CN(C)[CH:21]=[O:22].O>O1CCCC1>[Cl:1][C:2]1[C:3]([O:9][CH2:10][CH2:11][O:12][CH3:13])=[CH:4][CH:5]=[C:6]([F:8])[C:7]=1[CH:21]=[O:22]
Reactant: CN(C)C=O
Reactant: COCCOc1ccc(F)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COCCOc1ccc(F)c(C=O)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To 2-chloro-4-fluoro-1-(2-methoxy-ethoxy)-benzene (122, 1.50 g, 7.33 mmol) in tetrahydrofuran (44.0 mL), under an atmosphere of nitrogen at −78° C., n-butyllithium (2.50 M in hexane, 3.08 mL) was added slowly. After 15 minutes, N,N-dimethylformamide (0.681 mL, 8.80 mmol) was added to the reaction. After 30 minutes, the reaction was allowed to warm to room temperature. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give a light yellow solid (123, 1.20 g, 70.4%).
Reaction SMILES: [OH-].[Na+].[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:17][CH:18]([OH:25])[C:19]2[N:20]=[C:21]([NH2:24])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([O:5]C)=[O:4].O.Cl>O1CCOCC1.CO>[C:3]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:17][CH:18]([OH:25])[C:19]2[N:20]=[C:21]([NH2:24])[S:22][CH:23]=2)[CH3:15])=[CH:9][CH:8]=1)([OH:5])=[O:4]
Reactant: COC(=O)c1ccc(CC(C)N(Cc2ccccc2)CC(O)c2csc(N)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CO
Product: CC(Cc1ccc(C(=O)O)cc1)N(Cc1ccccc1)CC(O)c1csc(N)n1

Procedure:
13.6 ml (0.0136 mol) of 1N sodium hydroxide solution are added dropwise at room temperature to a solution of 1.5 g (0.0034 mol) of N-[2-(4-carbomethoxyphenyl)-1-methyl-ethyl]-N-benzyl-2-hydroxy-2-(2-amino-thiazol-4-yl)-ethanamine in dioxan/methanol=1:1 within 10 minutes, with stirring. After 1 hour 20 ml of water are added dropwise sufficiently slowly that a solution is always maintained. After 16 hours 13.5 ml (0.0136 mol) of 1N hydrochloric acid are added, and the mixture is extracted with methylene chloride which is dried over sodium sulphate and evaporated to dryness, and the resulting base is purified on a silica gel column using ethyl acetate/methanol=9:1.
Reaction SMILES: C([N:20]1[CH:24]=[C:23]([CH:25]2[CH2:34][C:33]3[CH:32]=[C:31]([NH2:35])[CH:30]=[CH:29][C:28]=3[CH2:27][CH2:26]2)[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.CO>CC(C)=O.C(OCC)C>[NH:20]1[CH:24]=[C:23]([CH:25]2[CH2:34][C:33]3[CH:32]=[C:31]([NH2:35])[CH:30]=[CH:29][C:28]=3[CH2:27][CH2:26]2)[N:22]=[CH:21]1
Reactant: Nc1ccc2c(c1)CC(c1cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn1)CC2
Agent: Cl
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: CO
Product: Nc1ccc2c(c1)CC(c1c[nH]cn1)CC2

Procedure:
A mixture of 5.5 g of the product obtained in Step 4, 3.8 ml of concentrated hydrochloric acid and 100 ml of methanol is heated at reflux for 2 hours. Following concentration of the solvent, the residue is taken up in an acetone/diethyl ether mixture. The precipitate is filtered off and yields the expected product.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:36]=[CH:35][C:12]([CH2:13][NH:14][CH2:15][CH2:16][CH2:17][C:18]4[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=4)[O:21][C:22]([CH3:31])([CH3:30])[C:23]([O:25]C(C)(C)C)=[O:24])=[CH:11][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.Cl[C:38]1[O:39][C:40]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[CH:41][N:42]=1>>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:10]=[CH:11][C:12]([CH2:13][N:14]([C:38]4[O:39][C:40]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)=[CH:41][N:42]=4)[CH2:15][CH2:16][CH2:17][C:18]4[CH:19]=[C:20]([CH:32]=[CH:33][CH:34]=4)[O:21][C:22]([CH3:30])([CH3:31])[C:23]([OH:25])=[O:24])=[CH:35][CH:36]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCCNCc2ccc(-c3noc(C4CC4)n3)cc2)c1
Reactant: Clc1ncc(-c2ccccc2)o1
Product: CC(C)(Oc1cccc(CCCN(Cc2ccc(-c3noc(C4CC4)n3)cc2)c2ncc(-c3ccccc3)o2)c1)C(=O)O

Procedure:
Similarly prepared from tert-butyl 2-[3-(3-{[4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)benzyl]amino}propyl)phenoxy]-2-methylpropanoate and 2-chloro-5-phenyl-oxazole (ref. GB1552125).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[C:9]([NH2:10])=[CH:8][C:7]2[O:11][CH2:12][CH2:13][O:14][C:6]=2[CH:5]=1.[CH:16]([NH2:18])=O>>[CH2:13]1[CH2:12][O:11][C:7]2[CH:8]=[C:9]3[C:4]([C:3](=[O:2])[NH:18][CH:16]=[N:10]3)=[CH:5][C:6]=2[O:14]1
Reactant: COC(=O)c1cc2c(cc1N)OCCO2
Reactant: NC=O
Product: O=c1[nH]cnc2cc3c(cc12)OCCO3

Procedure:
A mixture of 2.0 g. of 6-amino-3,4-ethylenedioxybenzoic acid methyl ester and 6 ml. of 99% formamide is refluxed for 1.5 hours, then cooled, diluted with 5 ml. of water and the resulting precipitate filtered off, water washed and dried to obtain 6,7-ethylenedioxyquinazolin-4(3H)-one, m.p. 275°C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:14])[CH3:13])[C:9]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30]>CN(C)C=O.ClCCl>[C:12]([C:10]1[C:9]([N:15]2[CH2:16][CH2:17][N:18]([CH2:28][C:29]([N:31]([CH3:33])[CH3:32])=[O:30])[CH2:19][CH2:20]2)=[C:8]2[C:3]([CH:4]=[CH:5][CH:6]=[N:7]2)=[C:2]([Cl:1])[CH:11]=1)(=[O:14])[CH3:13]
Reactant: CN(C)C(=O)CCl
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCN(CC(=O)N(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 50.7 %

Procedure:
To a mix of 1-(5-chloro-8-piperazin-1-ylquinolin-7-yl)ethanone (0.030 g, 0.10 mmol, from Example 47, Step 1) and potassium carbonate (0.043 g, 0.31 mmol) in N,N-dimethylformamide (1 mL) was added 2-chloro-N,N-dimethylacetamide (0.012 mL, 0.11 mmol). The reaction mixture was stirred at room temperature for 4 hrs, and then diluted with dichloromethane, washed with water, dried over MgSO4, concentrated and purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (19 mg, 49%). LCMS calculated for C19H24ClN4O2 (M+H)+: m/z=375.2; Found: 375.1.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH2:11][C:12]([NH:14][CH2:15][C:16]2[CH:32]=[CH:31][C:19]3[C:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:21][O:22][C:18]=3[CH:17]=2)=[O:13])=[N+:5]([O-:10])[C:6](Cl)=[CH:7][CH:8]=1)#[N:2].[F:33][C:34]([F:43])([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1)[CH2:35][NH2:36].C(Cl)Cl.O>CS(C)=O>[C:1]([C:3]1[C:4]([CH2:11][C:12]([NH:14][CH2:15][C:16]2[CH:32]=[CH:31][C:19]3[C:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[N:21][O:22][C:18]=3[CH:17]=2)=[O:13])=[N+:5]([O-:10])[C:6]([NH:36][CH2:35][C:34]([F:43])([F:33])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: NCC(F)(F)c1ccccn1
Reactant: CC(C)(C)OC(=O)Nc1noc2cc(CNC(=O)Cc3c(C#N)ccc(Cl)[n+]3[O-])ccc12
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1noc2cc(CNC(=O)Cc3c(C#N)ccc(NCC(F)(F)c4ccccn4)[n+]3[O-])ccc12

Procedure:
A mixture of 3-cyano-6-chloro-2-[3-(tert-butoxycarbonyl)amino-benzo[d]isoxazol-6-ylmethyl]aminocarbonylmethyl-pyridine 1-oxide (29 mg) and 2,2-difluoro-2-pyridin-2-yl-ethylamine (20 mg) (Organic Process Research & Development 8:192-200, 2004), in DMSO (0.5 mL) was heated overnight at 80° C. LC/MS (ESI) indicated the mono-Boc product (M+H+ 580.1) as the major component. To the reaction vial was added DCM (10 mL) and water (3 mL). The mixture was vigorously stirred. After removing the aqueous layer, the organic layer was further washed with water (4×3 mL) to remove DMSO and water soluble components. Rotary evaporation of solvent afforded a syrupy residue that was used without purification. LCAMS (ESI) showed the mono-Boc product (M+H+ 580.1) as the major component and the di-Boc product (M+H+ 680.0) as a minor component.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13].CS(O[CH:21]([CH3:34])[CH2:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])(=O)=O.O>C1(C)C=CC=CC=1>[C:24]1(=[O:33])[N:23]([CH2:22][CH:21]([N:11]([C:5]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=2[CH3:3])[S:12]([CH3:15])(=[O:14])=[O:13])[CH3:34])[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]12
Reactant: CC(CN1C(=O)c2ccccc2C1=O)OS(C)(=O)=O
Reactant: Cc1cccc(C)c1NS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(C)c1N(C(C)CN1C(=O)c2ccccc2C1=O)S(C)(=O)=O
Reaction time: 10 h
Yield: 23.8 %

Procedure:
0.15 g of a 80% mineral oil dispersion of sodium hydride are added in some portions to a solution of 1.0 g (5 mmoles) of N-(2,6-dimethylphenyl)-methanesulfonamide in 20 ml of dry toluene, and the mixture is heated to 100°-105° C. within one hour. A solution of 1.4 g (5 mmoles) of N-(β-methanesulfonyloxy-propyl)-phthalimide in 15 ml of toluene is added dropwise to the mixture within 0.5 hours at the same temperature, and the mixture is stirred then at 100°-105° C. for 10 hours. The mixture is cooled, 20 ml of water are added dropwise to it, thereafter the toluene phase is separated, washed twice with 10 ml of 1 n aqueous sodium hydroxide solution and thrice with 20 ml of water, each, dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure. The solid residue is triturated with dry diethyl ether. 0.46 g (23.8%) of crude 1-phthalimido-2-[N-(2,6-dimethylphenyl)-methanesulfonamido]-propane are obtained. The crude product is stirred at room temperature in 100 ml of diethyl ether for one hour to obtain a purified product melting at 196°-198° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O:13]N)([O-:3])=[O:2].CC1OCCC1.[N:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:23][CH:22]=1>>[N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[O-:13])([O-:3])=[O:2].[NH2:1][N+:21]1[CH:22]=[CH:23][C:24]([NH:27][C:28]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:34])=[CH:25][CH:26]=1
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1
Solvent: CC1CCCO1
Product: CC(C)(C)OC(=O)Nc1cc[n+](N)cc1
Product: O=[N+]([O-])c1ccc([O-])c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 3 L four-necked flask equipped with an overhead stirrer, thermocouple and a condenser was charged with O-(2,4-dinitrophenyl)hydroxylamine (I-37) (248 g, 1245.5 mmol) and 2-MeTHF (1 L). To the stirred suspension at room temperature were added tert-butyl pyridin-4-ylcarbamate (254.6 g, 1245.5 mmol) and 2-MeTHF (1 L). The mixture was stirred at room temperature for 10 minutes and slowly heated to 40° C. (after 30 minutes the suspension became a solution at 30° C.). An exotherm was observed at 40° C. and the temperature reached 45° C. without heating. The mixture was cooled with a water bath to 40° C. and stirred at 40° C. for 4 hours. The mixture was further cooled to room temperature and stirred for 15 hours. The batch was filtered and the solid was washed with MTBE (2×200 mL) and air dried to give 1-amino-4-(tert-butoxycarbonylamino)pyridinium 2,4-dinitrophenolate (I-38) as a yellow solid. 1H NMR (500 MHz, DMSO) δ 10.90 (s, 1 H), 8.62 (s, 1 H), 8.54 (d, 2 H), 7.91 (d, 2 H), 7.85 (m, 3 H), 6.30 (d, 1 H), 1.46 (s, 9 H).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@@H:17]2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:31]1[C@H:35]([CH2:36]Br)[CH2:34][CH2:33][C:32]1=[O:38].CCN(C(C)C)C(C)C>C(#N)C>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[CH2:20][CH2:19][C@@H:18]([NH:21][CH2:36][C@H:35]3[NH:31][C:32](=[O:38])[CH2:33][CH2:34]3)[C@@H:17]2[C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H](O[C@H]1CC[C@@H](N)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CC[C@@H](CBr)N1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O[C@H]1CC[C@@H](NC[C@@H]2CCC(=O)N2)[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 90 °C

Procedure:
To a solution of non-racemic 1-(S)-(1-(R)-(3,5-bis(trifluoro-methyl)phenyl)ethoxy)-2-(S)-(4-fluorophenyl)-3-(R)-(amino)cyclopentane from Example 39 in 0.5 mL of acetonitrile was added 50 mg of (2-pyrrolidon-5-(S)-yl)methylbromide and 0.10 mL of DIPEA. The reaction was heated in a sealed vial at 90° C. for 60 h and then evaporated. The residue was purified on a 2×1 mm preparative silica gel plates eluted with 2% TEA in methanol to afford 50 mg of title compound as a white solid. Mass spec (NH3 /CI): 533 (M+1).
Reaction SMILES: O.Cl.[Cl:3][C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][C:7]([N+:13]([O-])=O)=[CH:6][N:5]=1>C(O)C.[Fe]>[NH2:10][C:9]1[C:4]([Cl:3])=[N:5][CH:6]=[C:7]([NH2:13])[CH:8]=1
Reactant: O=[N+]([O-])c1cnc(Cl)c([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cnc(Cl)c(N)c1
Temperature: 80 °C
Reaction time: 0.03 h
Yield: 51 %

Procedure:
The mixture of 2.19 g of iron powder, 5 ml of water, and 10 ml of ethanol was stirred at 80° C. for 2 minutes. After incremental addition of 1 ml concentrated hydrochloric acid, the mixture was stirred at the same temperature until the solution became neutral. To the reaction solution was incrementally added suspension of 1 g 2-chloro-3,5-dinitropyridine in 5 ml ethanol, and the mixture was stirred at 80° C. for 40 minutes. The reaction solution was allowed to cool, and the iron was removed by filtration with celite, and the solvent of the filtrate was distilled off. Ethanol was added to the residue to disperse the solid content, and the solid content was collected by filtration to obtain 360 mg of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]1=[O:23].[Cl:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]2[O:35][CH2:36][O:37][C:31]=2[CH:30]=1>>[ClH:24].[CH2:36]1[O:35][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH2:27][CH2:26][CH2:25][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]3[CH2:7][CH2:8][N:9]3[CH2:18][CH2:17][C:16]4[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=4)[C:10]3=[O:23])=[CH:30][C:31]=2[O:37]1
Reactant: COc1cc2c(cc1OC)C(=O)N(CCC1CCCCN1)CC2
Reactant: ClCCCOc1ccc2c(c1)OCO2
Product: COc1cc2c(cc1OC)C(=O)N(CCC1CCCCN1CCCOc1ccc3c(c1)OCO3)CC2
Product: Cl

Procedure:
Prepared from 2-[2-(piperid-2-yl)-ethyl]-6,7-dimethoxy-1-oxo-1,2,3,4-tetrahydro-isoquinoline and 1-chloro-3-(3,4-methylenedioxy-phenoxy)-propane analogously to Example 1.
Reaction SMILES: [CH3:1][NH:2][NH2:3].C(N(CC)CC)C.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>ClCCl.C(OCC)(=O)C>[CH3:1][N:2]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH2:3]
Reactant: CCOC(=O)CBr
Reactant: CNN
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CN(C)N
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
To a solution of methylhydrazine 7.13 ml (150 mmol) and triethylamine 16.7 ml (120 mmol), ethyl 2-bromoacetate 16.7 g (100 mmol) in dichloromethane 50 ml was added and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate 300 ml and washed with brine 200 ml. The organic phase was dried over magnesium sulfate and filtered and the mother solution was concentrated in vacuo to obtain the title compound 10.2 g (77%).